The objective of this research program is to identify the mechanisms of neoplastic transformation in head and neck squamous cell carcinoma. We have focused on the epidermal growth factor receptor (EGFR) system because EGFR has been found to be constitutively active in high fraction of head and neck squamous cell carcinomas. It has been found that in addition to autophosphorylation, the activated receptor kinase also phosphorylates other specific intracellular proteins in the cell. It is believed that these intracellular substrates of EGFR kinase will then carry out the signal of EGF through a network of interacting proteins (or signal transduction pathways) that ultimately leads to cell proliferation or differentiation. Therefore, studies on these EGFR substrates will provide important information on the mechanisms of neoplastic transformation in head and neck squamous cell carcinoma. We have been investigating the nature of one of these receptor substrates, eps8. Our works have focused on the role of eps8 in EGFR signaling pathway and the biologic effect it imparts when switched on. We have evidences suggesting that eps8 is likely to play a role in the proliferation pathway of EGFR. We have also identified constitutively phosphorylation of eps8 in human tumor cell lines.